Project Summary/Abstract Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease of unknown etiology. The pathologic hallmarks of SLE (hereafter lupus also indicates SLE) are altered immune responses to autoantigens with autoantibody production and subsequent tissue injury. Previous studies, including our own, reported an increased frequency of IL-17 (IL-17a)-producing CD4+ T helper (Th17) cells in the peripheral blood of patients with SLE compared to that of healthy controls. Also, similar findings are reported in lupus-prone mice. However, previous studies that investigated neutralizing anti-IL-17 Abs in lupus-prone mice and IL-17-deficient lupus-prone mice showed mixed results, warranting further investigations. In addition, it is unknown whether the increased Th17 cells in lupus patients are different from Th17 cells in healthy people and can be selectively suppressed. Addressing these issues is critical in that it would lead to better defining the role of Th17 cells in the pathogenesis of lupus and targeting such cells therapeutically in lupus. The cytokine IL-27 is known to suppress IL-17 production from CD4+ T cells in mice and humans. Decreased levels of circulatory IL-27 are found in lupus patients, which may contribute to the increased Th17 cell response in lupus. Of interest, our preliminary study shows that lupus patients have higher levels of IL-27-mediated suppression of Th17 cells but not Th1 cells in vitro compared to age- and gender-matched healthy controls. Indeed, the frequencies of Th17 cells became similar in both groups in the presence of IL- 27 although patients with SLE had an increased frequency of Th17 cells in the absence of IL-27. Also, IL-27 suppressed additional cytokines including IL-21 and GM-CSF, which can be involved in lupus. Although the exact mechanism of this finding is yet to be elucidated, the transcription factor IRF8 can be a factor responsible for IL-27-mediated suppression of the cytokines since IL-27 induces the up-regulation of IRF8 in CD4+ T cells and IRF8 is known to suppress IL-17 and GM-CSF in mice. Based on these findings, we hypothesize that Th17 cells in lupus patients have distinct traits, including the susceptibility to IL-27-mediated suppression, and that IL-27 can improve disease activity in lupus by suppressing Th17 cell response dependently of IRF8. The goal of our proposal is to test these hypotheses by analyzing the immune cells of lupus patients and healthy controls in vitro as well as exploring the possible therapeutic effect of IL-27 and its mechanism through IRF8 in lupus-prone mice. The results of our study will lead to the development of new approaches in treating lupus patients.